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Addition of plant sterols and stanols to food: assessment of a new study fromthe Netherlands
BfR opinion 006/2012, 1 December 2011
Plant sterols and stanols are added to foods such as margarine, milk and bread, because of
their cholesterol-lowering effect. Most foods with such additives are novel foods which must
accordingly be assessed and approved in terms of their potential health risks.
Plant sterols are found in low quantities in all fatty plant-based foods such as oils, nuts,
seeds and cereals. For humans, they are not essential and are hardly used in the humanmetabolism. Plant stanols are hydrolysed plant sterols which are not naturally present inplant-based foods.
The Federal Institute for Risk Assessment (BfR) below assesses a study from theNetherlands which provides valuable information on the unwanted effects of plant sterols on
human retinal microvessels. Retinal vessels analysis is increasingly used for early diagnosisof cardiovascular risks. The findings of the study indicate that intake of plant sterols may
entail cardiovascular risks for healthy persons who consume foods containing plant sterols in
relatively large quantities and over a long period of time. Due to the amount of data available,
the extent of this potential risk cannot currently be quantified.
The BfR has already pointed out in earlier opinions that foods to which plant sterols or
stanols are added are largely consumed by persons who do not have increased cholesterollevels as well as by children. The European Food Safety Agency currently recommends thatdaily consumption of plant sterols and stanols be limited to three grams.
In view of the results of the Dutch study, the BfR is of the opinion that the use of plant sterols
as a food additive should be reassessed at the European level.
1 Subject of the Assessment
The study “Effects of long-term plant sterol and stanol consumption on the retinal
vasculature: A randomized controlled trial in statin users” by Kelly, Plat, Mensink andBerendschot was published in the magazine Atherosclerosis 214 (2011) 225–230. Resultsfrom this study indicate that the consumption of foods containing plant sterols has unwanted
effects on human retinal microvessels. The BfR has evaluated the relevance of the described
effects on behalf of the Federal Ministry of Food, Agriculture and Consumer Protection(BMELV).
2 Findings
Focusing on persons taking statin medication while at the same time eating margarine
containing phytosterols or phytostanols, the study “Effects of long term plant sterol and stanol
consumption on the retinal vasculature: A randomized controlled trial in statin users“ found asignificant correlation between the campesterol concentration in the blood plasma and thethickness of veins in the retina after 85 weeks. This correlation was independent of thesimultaneous reduction of the LDL cholesterol level. An increase in the diameter of the retinal
vessels is being discussed as an early risk marker for cardiovascular disease.
This means that findings from experiments on humans are available for the first time everwhich may indicate the independent atherogenic potential of slightly elevated plasmaPage 1 of 6

Federal Institute for Risk Assessment
www.bfr.bund.dephytosterol concentrations. However, the extent to which the consumption of phytosterol
margarine in test persons actually influences the risk of developing cardiovascular diseasecannot be assessed. Based on the findings of this study, it nevertheless seems possible that
there is an increased atherogenic risk, especially for persons who regularly eat foods withplant sterol additives and who cannot expect any advantage from lowering the cholesterollevel.
The study “Consumption of plant sterols in Belgium: consumption patterns of plant sterolenriched foods in Flanders Belgium” by Sioen and colleagues, published in the British
Journal of Nutrition (2011), 105, 911–918, reports that of the Flemish population, 21% of preschool children and 28% of adults eat foods containing phytosterol. In that particular survey,
more than half of the adult consumers who knew what their cholesterol level was stated thatthey had no elevated cholesterol level.
Despite its local nature, the Belgium consumption study nevertheless confirms that foods
with phytosterol addition are largely eaten by healthy persons including children with normalcholesterol levels. In view of the experimental and epidemiological indications thatphytosterols have a potentially harmful effect on vessels, the BfR holds that there is currently
insufficient evidence of the safety of such foods for healthy persons, especially children.
The BfR therefore recommends that the Federal Ministry of Food, Agriculture and Consumer
Protection (BMELV) contact the EU Commission, so that the latter commissions theEuropean Food Safety Authority (EFSA) to conduct a new assessment of phytosterols asfood fortifier. Furthermore, the BfR recommends that suitable management measures betaken to ensure that the consumption of such foods is restricted to people with increasedcholesterol levels and that healthy individuals, especially children, do not eat foods withphytosterol addition on a regular basis.
3 Statement of Reasons
The study “Effects of long term plant sterol and stanol consumption on the retinal
vasculature: A randomized controlled trial in statin users” touches on the question to what
extent plant sterols must be construed as an independent risk factor for the genesis ofcardiovascular disease. On this question, the BfR had already made the following statements
in 2004:a) There are indications but no conclusive chain of evidence to support the hypothesis thatphytosterols can contribute to the genesis of coronary heart disease even in slightly elevatedplasma concentrations.
b) The hypothesis results from
¾ the correlation between early coronary incidents with very high phytosterol levels in
the plasma of phytosterolaemics and¾ the observation that early coronary incidents in coronary heart disease test persons
correlate with familiar hypercholesterolaemia with plasma phytosterol concentrationsin the upper segment of normal distribution.
In its opinion from 21 April 2005, the NDA panel of the EFSA (Panel on Dietetic Products,
Nutrition and Allergies) commented that this issue had been done sufficient justice in theexisting safety assessments of phytosterols as part of the novel food applications (EFSA,2005).
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www.bfr.bund.deSince then, however, several studies have been published which reported a positive
correlation between the phytosterol concentration in the plasma and the incidence of
cardiovascular disease (coronary heart disease) (Assmann et al., 2006; Rajaratnam et al.,2000 and Thiery et al. ,2006). Nevertheless, epidemiological studies with opposite results
have also appeared (BfR, 2008). In addition, the study “Genetic Regulation of Serum
Phytosterol Levels and Risk of Coronary Artery Disease“ by D. Teupser and J. Thiery fromthe University of Leipzig with contributions from 42 other authors from both national andinternational institutions appeared in August 2010 in “Circulation: Cardiovascular Genetics”, amagazine published by the American Heart Association. This study reported on theidentification of certain genetic polymorphisms which were concordant and associated in astatistically significant way with the serum level of plant sterols and with the incidence of
cardiovascular disease. The fact that two of the identified polymorphisms concern a gene of
the sterol transport protein ABCG5/8 can be seen as an indication of a possible causal link.
The congenital functional loss of this transport protein is known as the cause for thecongenital metabolic disorder phytosterolaemia which is characterised by very highphytosterol plasma concentrations and a high risk of premature heart attack (Sudhop andBergemann, 2004).
Based on a population of test persons taking statin medication (18 to 65 years of age), thestudy “Effects of long term plant sterol and stanol consumption on the retinal vasculature: A
randomized controlled trial in statin users” investigated the influence of phytosterols andphytostanols on human retinal vessels. The retinal vessels form part of microcirculation andare accessible by non-invasive optical methods, meaning that the vessel diameter can bemeasured with optoelectronic methods such as eye fundus photography with electronic
image interpretation. Although cardiovascular disease (coronary heart disease) essentiallydenotes diseases of the large vessels, some studies have shown a significant correlation
between the diameter of the retinal vessels (especially the veins) as well as the quotient of
the artery and vein diameter (A/V quotient) and established cardiovascular parameters
including deadly heart attacks (Wong et al., 2002, Ikram et al., 2004; Wang et al., 2002 andMcGeechan et al., 2008). Retinal vessels analysis is therefore increasingly used for early
diagnosis of cardiovascular risks.
The test persons examined by means of eye fundus photography neither had elevated bloodpressure nor increased blood sugar levels. However, in order to lower their cholesterol level,
they had been treated with statin-type cholesterol synthesis inhibitors for some time past. In
the study, they were additionally given half-fat margarine for 85 weeks. This margarine either
contained 2,5 g phytosterols (eleven test persons), 2.5 g Phytostanols (eight subjects) or no
added plant sterols or stanols (11 test persons) per daily intake (30 g). Apart from eye fundus
photography, the test person’s plasma concentrations for various sterol compounds before
and after the intervention were also measured.
All test persons who were given margarines with phytosterols or phytostanols showed asignificant reduction of the LDL cholesterol level by approximately 10% compared to thecontrol group. At the same time, cholesterol synthesis was, despite statin medication,
significantly higher in both groups than it was in the control group. For 11 of the test persons
who received phytosterol margarine, the plasma concentrations for campesterol and ß sito
sterol (in relation to cholesterol) rose by 110 % and 44 % respectively, whereas bothconcentrations were reduced by 14.3 and 6.8 % respectively in test persons who received
phytostanols. The basal plasma concentrations of campestanol and sitostanol were about
100 times lower for the test persons in all groups than then basal phytosterol concentrations.
Although, for the test persons who took phytostanols for 85 weeks, the campestanol andSeite 3 von 6Federal Institute for Risk Assessment
www.bfr.bund.desitostanol plasma concentrations rose ten-fold and six-fold respectively, they still remained
lower overall than the initial phytosterol concentrations in all groups.
In the eye fundus photographs of all test persons which were taken before and after theintervention, the diameters of four retinal arteries and four retinal veins were measured foreach subject. In addition, the difference between the post-intervention values and the initialvalues was determined. In direct comparison to the intervention groups, no statisticallysignificant changes in the vessel diameter were found. However, a trend towards an increaseof the vein diameter and towards a decrease of the A/V quotient was observed in thephytosterol group compared to the two other groups. In addition, the evaluation of the veindiameter in dependence of the phytosterol level across all individuals in two statisticalregression models showed a significant positive correlation of the vein diameter with thecampesterol concentration (in relation to cholesterol) in the blood plasma.
The authors interpret the results of the study as an indication of a possible detrimental effectof phytosterols on vessels which a) exists independently of any reduction of the cholesterollevel and b) would have to be verified by additional studies.
This study for the first time presents findings based on experiments with humans which showthat a food-based increase of the plant sterol plasma level has a detrimental influence on therisk parameter for coronary heart diseases independently of the reduction of the LDLcholesterol level. Although the analysis of the microvessels of the retina for an earlyrecognition of cardiovascular risks has not been fully established, this method is alreadywidely used in medical research / practice. This study does not permit any statement yet on
the question whether the consumption of plant sterols does indeed increase the risk of aheart attack in test persons affected by changes in the retinal vessels or whether, due to thereduction of the cholesterol level, a positive net effect is to be expected. Here it is necessary
to wait for the results of studies which investigate the influence of the consumption of foods
containing phytosterols on clinical endpoints.
In addition, it cannot be excluded that the vessels of the examined subjects were alreadyaffected by their underlying disease. For this reason, it would have to be investigatedwhether healthy persons also react to a food-based increase of the plasma phytosterol
concentrations with changes in the diameter of the retinal microvessels.
Overall, even this study does not furnish sufficient data to allow a final assessment of theatherogenic potential of slightly increased phytosterol plasma concentrations. However,within the context of the totality of studies suggesting independent atherogenic potential ofphytosterols, this study provides further indications of the existence of such a risk. Especiallyfor healthy persons who start consuming such foods on a regular basis as children an
increased atherogenic risk seems possible.
For Germany it was found that 3.5 % of the users of foods containing phytosterols areunderage children who were not known to have elevated cholesterol levels (Niemann et al.,2007). In Belgium, a recent food consumption study established that 21 % of pre-school
children in a Flemish region also eat foods containing phytosterols and that for 58 % of adultconsumers of such foods who know what their cholesterol level is, that level was notelevated (Sioen, et al., 2011). These figures show that the mandatory labelling of foods
containing added plant sterols is not a sufficient measure to ensure that the consumption ofsuch foods is restricted to people with elevated cholesterol levels.
4 Framework of Action / Measures
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The BfR suggests that the EFSA is commissioned to carry out a reassessment ofphytosterols added to foods. Furthermore, the BfR recommends that suitable management
measures be taken to ensure that the consumption of such foods is restricted to people withincreased cholesterol levels and that healthy individuals, especially children, do not eat foods
with phytosterol addition on a regular basis.
5 References
Assmann G, Cullen P, Erbey J, Ramey DR, Kannenberg F, Schulte H. Plasma sitosterolelevations are associated with an increased incidence of coronary events in men: results of anested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study.
Nutr Metab Cardiovasc Dis. 2006 Jan; 16(1):13-21.

BfR 2008, Menschen mit normalen Cholesterinwerten sollten auf den Verzehr vonLebensmitteln mit zugesetzten Pflanzensterinen verzichten, Stellungnahme vom
3. September 2008
EFSA 2005, Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on arequest from the Commission related to two scientific publications concerning aspects ofserum levels of phytosterols. Adopted on 21th April 2005.
Ikram MK, de Jong FJ, Vingerling JR, et al. Are retinal arteriolar or venular diameters
associated with markers for cardiovascular disorders? The Rotterdam Study. Invest
Ophthalmol Vis Sci 2004; 45:2129–34.
Kelly ER, Plat J, Mensink RP, Berendschot TT. Effects of long term plant sterol and -stanol
consumption on the retinal vasculature: a randomized controlled trial in statin users.
Atherosclerosis. 2011 Jan; 214(1):225-30.
McGeechan K, Liew G, Macaskill P, Irwig L, Klein R, Sharrett AR, Klein BE, Wang JJ,
Chambless LE, Wong TY. Risk prediction of coronary heart disease based on retinal
vascular caliber (from the Atherosclerosis Risk In Communities [ARIC] Study). Am J Cardiol.
2008 Jul 1; 102(1):58-63.
Niemann B., Sommerfeld C., Hembeck A. and C. Bergmann Plant sterol enriched foods asperceived by consumers, BfR-Wissenschaft 05/2007
Rajaratnam RA, Gylling H, Miettinen TA. Independent association of serum squalene andnoncholesterol sterols with coronary artery disease in postmenopausal women. J Am CollCardiol. 2000 Apr; 35(5):1185-91.
Sioen I, Matthys C, Huybrechts I, Van Camp J, De Henauw S. Consumption of plant sterols
in Belgium: consumption patterns of plant sterol-enriched foods in Flanders, Belgium. Br JNutr. 2011 Mar; 105(6):911-8.
Sudhop T, von Bergmann K. Sitosterolemia--a rare disease. Are elevated plant sterols anadditional risk factor? Z Kardiol. 2004 Dec; 93(12):921-8. Review.
Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C, Holdt LM, Leichtle A, Greiser
KH, Huster D, Linsel-Nitschke P, Schäfer A, Braund PS, Tiret L, Stark K, Raaz-Schrauder D,Fiedler GM, Wilfert W, Beutner F, Gielen S, Grosshennig A, König IR, Lichtner P, Heid IM,
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Kluttig A, El Mokhtari NE, Rubin D, Ekici AB, Reis A, Garlichs CD, Hall AS, Matthes G,
Wittekind C, Hengstenberg C, Cambien F, Schreiber S, Werdan K, Meitinger T, Loeffler M,Samani NJ, Erdmann J, Wichmann HE, Schunkert H, Thiery J. Genetic regulation of serum
phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet. 2010 Aug;3(4):331-9.
Thiery J, Ceglarek U., Fiedler GM, Leichtle A, Baumann S, Teupser D, Lang O, Baumert J,
Meisinger M, Loewel H, and Doering A. Abstract 4099: Elevated Campesterol Serum
Levels - a Significant Predictor of Incident Myocardial Infarction: Results of thePopulation-based MONICA/KORA Follow-up Study 1994 to 2005 Circulation, Oct 2006;
114: II_884.
Wang JJ, Liew G, Wong TY, Smith W, Klein R, Leeder SR, Mitchell P. Retinal vascularcalibre and the risk of coronary heart disease-related death. Heart. 2006 Nov;92(11):1583-7.
Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Tielsch JM, Klein BE, Hubbard LD.
Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The
Atherosclerosis Risk in Communities Study. JAMA. 2002 Mar 6; 287(9):1153-9.

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